Conference 19 - 2015 Case: 04 20160330

Signalment:

12-year-old, female spayed, domestic shorthair cat, feline (Felis domestics).The cat was presented to an animal shelter with a history of vomiting and anorexia. Upon physical examination, she was thin with pale mucous membranes. The abdomen was distended, and hepatomegaly was palpated. The cat underwent exploratory laparotomy, and representative samples of liver, as well as the lesions in the greater omentum and parietal peritoneum were collected for histopathologic evaluation. However, the cat was euthanized due to poor prognosis.

Gross Description:

The abdominal cavity contained blood, and clotted blood and fibrin tags covered the surface of the liver.

Hepatic architecture was also extensively effaced and expanded by multiple, coalescing, umbilicated, firm, pale tan nodules (5-20mm diameter) that extended across the surface and throughout the parenchyma. Firm, pale tan, coalescing nodular lesions (3-10mm diameter) also extended to involve the greater omentum and parietal peritoneum.

Histopathologic Description:

Liver: The hepatic parenchyma is extensively necrotic and effaced by focal to coalescing proliferations of neoplastic cells that differentiate toward biliary epithelium and form acini, tubules, and packets. Cells are low cuboidal to columnar with indiscrete borders, and pale amphophilic, vacuolated cytoplasm. Nuclei are large, round to oval, and contain one or two prominent nucleoli. There are 2-4 mitotic figures per ten 40x objective fields. Neoplastic ducts and acini contain luminal neutrophils, proteinaceous fluid, and cell debris, and are embedded within an extensive background collagenous stroma (scirrhous response). Neoplastic cells are present in lymphatics, and along the capsular surface in some regions (not present in all sections). Blood vessels and sinusoids contain fibrin thrombi. Scattered neutrophils are present throughout the necrotic tissue. Mesothelial cell proliferation is also seen along the capsular surface.

Within the adjacent remaining parenchyma, portal regions are expanded by moderate proliferations of lymphocytes & plasma cells, with bile duct proliferation, and periductular fibrosis. Some bile ducts are lined by attenuated epithelium and contain luminal or periductal neutrophils.

Morphologic Diagnosis:

Liver: Cholangiocellular carcinoma with lymphatic invasion; Chronic fibrosing, lymphoplasmacytic portal hepatitis, domestic shorthaired cat, feline.

Lab Results:

Serum biochemistry abnormalities: Total protein 8.9 g/dL (5.8-8.1); Albumin 1.8 g/dL (2.6-4.0); Alanine aminotransferase 240 U/l (15-52); Aspartate aminotransferase 112 U/l (14-42); Bilirubin 4.5 mg/dL (0-0.6). Hematologic abnormalities: Hematocrit 18% (24-45); Hemoglobin 6.5 g/dL (8.0-15.0); Red blood cell count 4.37 M/μL (5.0-10.0).

Condition:

Cholangiocellular carcinoma

Contributor Comment:

Cholangio-cellular carcinomas are malignant neoplasms that can occur in all species. They arise from bile duct epithelium, predominantly from intrahepatic ducts, although extrahepatic ducts can be involved also. These neoplasms can present either in the form of a mass or as coalescing, umbilicated, nodular proliferations on the surface of the liver and throughout the parenchyma.^7,11

Although primary hepatobiliary tumors are rare in cats, cholangiocellular carcinoma represents the most common non-hematopoietic, hepatic malignancy in this species.¹This is a locally aggressive neoplasm with a high metastatic potential, and metastases are documented in up to 80% of necropsy cases.⁸ Extrahepatic metastasis is common, especially to cranial abdominal lymph nodes and lung, and seeding of tumor into the abdominal cavity is not uncommon, with lesions extending throughout the mesentery and visceral peritoneal surfaces.¹¹

In cats, cholangiocellular carcinomas are typically found in animals of 9 years of age and older.¹ There are no breed predilections, and although there are some suggestions that this tumor is more commonly diagnosed in male cats,¹other studies do not demonstrate such a gender difference.⁶The prognosis is poor, with a life expectancy of less than 6 months.⁶

As compared with cats with benign tumors of the biliary tract, cats with cholangiocellular carcinoma are more likely to exhibit clinical signs, and lethargy, anorexia, and vomiting are most commonly reported.¹Upon physical examination, the most common finding is the presence of a cranial abdominal mass or hepatomegaly, while ascites and icterus are less common.¹

Hematologic and biochemical profiles are often nonspecific.¹Leukocytosis is so-metimes reported, and alanine amino-transferase, aspartate aminotransferase, and total bilirubin levels may be elevated.⁶

Microscopically, these tumors are usually distinctly adenocarcinomatous, comprising proliferations of cells that differentiate toward biliary epithelial cells, and form acini, tubules, and papillary projections. More poorly differentiated forms may be composed of solid epithelial proliferations, with or without the formation of islands, cords, or packets of cells, and foci of squamous differentiation. Numerous mitotic figures are present. A variable connective tissue stroma is present, often with marked collagen deposition, the so-called scirrhous response. Areas of necrosis are also common.^7,11

Paraneoplastic alopecia has also been associated with cholangiocellular carcinoma, as well as pancreatic adenocarcinoma in cats. This presents as bilaterally symmetrical alopecia of the ventrum and limbs, sometimes with a shiny appearance to the alopecic skin. Histologically, skin changes comprise follicular and adnexal atrophy with hypoplasia of the stratum corneum.⁹

In people, cholangiocellular carcinoma is the second most common hepatic malignancy after hepatocellular carcinoma, accounting for more than 7% of cancer deaths throughout the world. In the United States, it accounts for 3% of all cancer deaths, and its prevalence is highest in Hispanics. Although most cholangiocellular carcinomas in the western world arise without evidence of antecedent disease, chronic hepatobiliary inflammatory conditions can predispose patients to development of these tumors. The incidence rates of this malignancy are highest in Southeast Asia, where a major risk factor is chronic infection of the biliary tract with the liver fluke Opisthorchis sinensis. Additional predisposing risk factors for development of cholangiocellular carcinoma in people, include: primary sclerosing cholangitis; infection with hepatitis B or C; and congenital diseases of the biliary tract, such as choledochal cysts or Carolis syndrome.^4,5 However, no definitive association between inflammatory hep-atobiliary disease, or other antecedent conditions, has been established in cats.

JPC Diagnosis:

1. Liver: Cholangiocellular carcinoma.

2. Liver: Cholangiohepatitis, suppurative, multifocal, severe, with septic thrombi and telangiectasis.

Conference Comment:

As mentioned above, in certain regions of Southeast Asia there is a link between cholangiocellular carcinoma in people and infection with liver flukes, including Opisthorchis viverrini. The fluke is classified as a group 1 carcinogen, and the infective stage can be transmitted by consumption of undercooked fish. Once in the digestive tract of the definitive host, the

parasites migrate to the bile ducts where they feed on biliary epithelium. The carcinogenicity of fluke infection is driven by multiple factors, including mechanical damage to biliary epithelium, inflammatory processes driven by cytokines such as IL-6, and parasite excretory products found within host cholangiocytes which have the ability to drive cell proliferation. The fluke O. viverrini is capable of secreting extracellular vesicles, which are small membrane bound structures released from different types of helminths. The vesicles are taken up by cholangiocytes resulting in both infla-mmatory and protumorigenic changes providing a mechanism by which the parasite is able to drive tumorigenesis. Vesicle uptake is documented to result in dysregulation of protein expression involved in wound healing, tumor cell invasion and the proteasome complex.² Liver fluke carcinogenesis has not been documented in domestic food animals, such as sheep and cattle; this may be due to interspecies dif-ferences in immunomodulatory mechanisms or uptake of procarcinogenic secretory products, or perhaps because of differences in lifespan. Infection with the biliary fluke Platynosomum fastosum in cats, which results in varying degrees of inflammation, fibrosis and hyperplasia within the biliary tract, has been found concurrently with cholangiocarcinoma in some animals.³

In this slide, the lobular hepatic architecture is approximately 75% effaced. Concentric fibrosis surrounding bile ducts is a prominent feature, and the moderator commented this feature is secondary to cholestasis, and neutrophilic cholangitis is, in turn, the result of biliary stasis.

Fibrin thrombi within sinusoids and blood vessels contain enmeshed epithelioid macrophages and other inflammatory cells. In this slide, large areas of sinusoidal dilation border fibrin thrombi. These areas of dilation may represent local blood flow change or, in the normal liver, would often be interpreted as foci of telangiectasis, a common histologic finding in the liver of the cat.

Additionally, two important diagnostic features in this case include the scirrhous reaction and mucous within ducts / tubules, which are not seen in hepatocellular carcinoma. In domestic animal species, metastatic neoplasia in the liver is more common than primary neoplasia.¹⁰

References:

1. Balkman C. Hepatobiliary neoplasia in dogs and cats. Vet Clin North Am Small Anim Pract. 2009; 39:617-25.

2. Chaiyadet S, Sotillo J, Smout M, Cantacessi C, et al. Carcinogenic liver fluke secretes extracellular vesicles that promote cholangiocytes to adopt a tumorigenic phenotype. J Infect Dis. 2015; 212(10):1636-45.

3. Cullen JM, Stalker MJ. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. 6th ed. Vol 2. St. Louis, MO: Elsevier; 2016:322.

4. Friman S. Cholangiocarcinoma – current treatment options. Scand J Surg. 2011; 100:30-34.

5. Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran, Pathologic Basis of Disease. 8th ed. Elsevier; 2010:880-881.

6. Lawrence HJ, Erb HN, Harvey HJ. Nonlymphomatous hepatobiliary masses in

cats: 41 cases (1972 to 1991). Vet Surg. 1994; 23:365–368.

7. Maxie MG. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. 5th ed. Vol 2. Philadelphia, PA: Elsevier; 2007:385-386.

8. Patnaik AK. A morphological and immunocytochemical study of hepatic

neoplasms in cats. Vet Pathol. 1992; 29:405–415.

9. Tasker S, Griffon DJ, Nuttall TJ, et al. Resolution of paraneoplastic alopecia following surgical removal of a pancreatic carcinoma in a cat. J Small Anim Pract. 1999; 40:16-19.

10. World Small Animal Veterinary Association. Standards for the Clinical and Histologic Diagnosis of Canine and Feline Liver Diseases. Philadelphia, PA: Saunders Elsevier; 2006.

11. Zachary JF, McGavin MD. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis; Mosby Elsevier; 2012:444.